The invention relates to novel gossylic compounds which retain clinical efficacies of gossypol and derivatives thereof, while exhibiting significantly lower toxicity.
1. Field of the Invention
Gossypol is a yellow pigment from the cotton plant of the formula: ##STR1##
Gossypol has several potentially useful biological activities, including antiviral, antimalarial, antiparasitic, and contraceptive activity. Of particular interest is gossypol's recognized antiviral activity against enveloped viruses including HIV. Gossypol, however, is significantly cytotoxic at effective dosage levels for studied clinical applications, particularly antiviral activity, and the native compounds thus have had little clinical importance.
Gossypol toxicity has been associated with the 8,8'-dicarboxaldehyde groups, stimulating interest in derivatives or analogs in which the aldehyde groups have been derivatized to provide compounds which retain a substantial amount of the desirable biological activity of the parent compounds, while exhibiting decreased cytotoxicity.
2. Description of Related Art
Gossylic compounds wherein the aldehyde groups of gossypol have been modified in attempts to reduce toxicity of the parent compound have been prepared. However, the production of stable derivatives of gossypol in which only the aldehyde groups are modified has been limited because the sensitive phenolic hydroxyl groups in the 1,1'0 (peri) positions complicate the chemistry for modification of these groups (see, e.g., Chem.Rev. 60:555-574, 1960). On the theory that free peri hydroxyl groups might not be important for at least some of the biological activities of gossypol, including its anti-HIV activity, processes for derivatizing gossypol to block aldehyde functionality and reduce cytotoxicity have been developed wherein the peri hydroxyls are protected, or incorporated into the functional group replacing the aldehyde during synthesis. Such derivatizations of gossypol include the protection of the gossypol 1,1'-hydroxyl groups with acyl groups to provide gossylic nitrites as described in U.S. Pat. No. 4,806,568 to Vander Jagt et al.; the incorporation of the gossypol aldehyde groups into lactone or iminolactone functional groups which replace the aldehyde groups in gossylic (imino)lactones as described in U.S. Pat. No. 5,026,726 to Vander Jagt, et al.; and the derivatives described in J.Med.Chem. 26:1799-1801 (1986) and Pharmacol.Res. 24:407-412 (1991). Each of these references is incorporated herein by reference.
Some of these gossypol derivatives have proved biologically useful, particularly gossylic iminolactone (GIL), of the formula: ##STR2## As a group, however, these derivatives do not provide the broadest range of functionality, as modified peri hydroxyl groups are always present. Further, processes for making hemigossypol derivatives using gossypol as a starting material are not believed to be known in the prior art. It is accordingly desirable to provide a de novo synthesis from simple precursors of gossypol analogs, including hemigossypol, which lack the gossypol peri hydroxyl groups.